3D molecular MR imaging of liver fibrosis and response to rapamycin therapy in a bile duct ligation rat model.
3D molecular MR imaging of liver fibrosis and response to rapamycin therapy in a bile duct ligation rat model.
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DOI：
10.1016/j.jhep.2015.04.029
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发表时间：
2015-09
影响因子：
25.7
通讯作者：
Caravan P
中科院分区：
文献类型：
--
作者：
Farrar CT;DePeralta DK;Day H;Rietz TA;Wei L;Lauwers GY;Keil B;Subramaniam A;Sinskey AJ;Tanabe KK;Fuchs BC;Caravan P
肝活检是评估肝纤维化的金标准，由于采样误差和侵入性而受到限制。因此，迫切需要一种方法来非侵入性地量化整个肝脏的纤维化。本研究的目的是利用I型胶原的分子磁共振成像（MRI）对肝纤维化进行无创成像，并评估对雷帕霉素治疗的反应。胆管结扎法（BDL）诱导大鼠肝纤维化。在BDL后4、10或18天进行MRI检查。一些BDL大鼠从第4天开始每天用雷帕霉素治疗，第18天成像。采用三维（3D）反转恢复MRI序列量化胶原靶向探针EP-3533诱导的肝脏纵向松弛率变化（ΔR1）。肝组织进行纤维化病理评分，分析天狼星红染色和羟脯氨酸含量。与对照组相比，ΔR1随着BDL后时间的推移而显著增加，这与体外纤维化增加的测量结果一致。受试者工作特征曲线分析表明ΔR1能够检测肝纤维化并区分中晚期纤维化。与胶原比例面积（CPA）标准相比，EP-3533 MRI正确表征了12只治疗大鼠中11只对雷帕霉素的反应。3D MRI能够表征整个肝脏的疾病异质性。EP-3533允许肝纤维化分期，评估对雷帕霉素治疗的反应，并证明了检测肝纤维化异质性的能力。
Liver biopsy, the gold standard for assessing liver fibrosis, suffers from limitations due to sampling error and invasiveness. There is therefore a critical need for methods to non-invasively quantify fibrosis throughout the entire liver. The goal of this study was to use molecular Magnetic Resonance Imaging (MRI) of Type I collagen to non-invasively image liver fibrosis and assess response to rapamycin therapy. Liver fibrosis was induced in rats by bile duct ligation (BDL). MRI was performed 4, 10, or 18 days following BDL. Some BDL rats were treated daily with rapamcyin starting on day 4 and imaged on day 18. A three-dimensional (3D) inversion recovery MRI sequence was used to quantify the change in liver longitudinal relaxation rate (ΔR1) induced by the collagen-targeted probe EP-3533. Liver tissue was subjected to pathologic scoring of fibrosis and analyzed for Sirius Red staining and hydroxyproline content. ΔR1 increased significantly with time following BDL compared to controls in agreement with ex vivo measures of increasing fibrosis. Receiver operating characteristic curve analysis demonstrated the ability of ΔR1 to detect liver fibrosis and distinguish intermediate and late stages of fibrosis. EP-3533 MRI correctly characterized the response to rapamycin in 11 out of 12 treated rats compared to the standard of collagen proportional area (CPA). 3D MRI enabled characterization of disease heterogeneity throughout the whole liver. EP-3533 allowed for staging of liver fibrosis, assessment of response to rapamycin therapy, and demonstrated the ability to detect heterogeneity in liver fibrosis.